The expression of specific immune responses in lung parenchyma is important for host-defense against the injurious effects of antigenic agents deposited in lungs. Impaired immune responses result in pulmonary infections; exaggerated responses contribute to lung injury. The long-term objectives of this ongoing research project are to define the cellular events responsible for expression of immune responses in lung tissue, and to characterize the mechanisms that generate and regulate pulmonary immune responses. Work already performed has resulted in the development of both hypothetical and experimental models for detailed analysis of cellular and molecular processes that regulate immune responses in lung parenchyma of mice. The specific aims of this proposal will examine regulatory mechanisms in this model. Project I will test the hypothesis that stimulation of alveolar macrophages enhances immune responses by increasing Ia-expression and antigen presentation. Normal alveolar macrophages will be stimulated to increase their expression of Ia. Their abilities to present antigen in vitro or to induce pulmonary immune responses in vivo will be measured and correlated with Ia-expression. Project 2 will test the hypothesis that the composition and states of activation of lymphocyte subsets that traffic into lungs modulate pulmonary immune responses. The kinetics, sequence of appearance, and states of activation of lymphocyte subsets that enter lungs during immune responses will be determined by flow cytometry. To define initial steps of lymphocyte traffic into the lung, lymphocyte binding to pulmonary vascular endothelium will be examined. Project 3 will test the hypothesis that host factors influence pulmonary immune responses in intact mice. In some experiments, pulmonary fibrosis will be induced by treatment of mice with bleomycin. In other studies, lymphocyte subsets will be selectively depleted with appropriate monoclonal antibodies. The effects of either pulmonary fibrosis or of selective immune deficiency on pulmonary immune responses will be quantitated using established assay systems. Results of these studies will further elucidate the cellular basis for the generation and regulation of immune responses in lung tissue. Consequently, they will provide a better understanding of the mechanisms of immune defense of the lung against infection and of the pathogenetic mechanisms leading to lung injury.